Type 1 diabetes (T1D) is an autoimmune metabolic disease characterized by destruction of pancreatic beta cells. Among numerous chromosomal regions that are linked to disease risk, the HLA locus has by far the strongest disease association. In particular, subjects who are heterozygous for HLA- DQA1*0301/DQB1*0302 (DQ8) and HLA-DQA1*0501/DQB1*0201 (DQ2) have the highest risk. In contrast, HLA- DQA1*0102/DQB1*0602 (DQ6) is associated with disease protection. While these genetic aspects are well established, the functional mechanisms by which DQ molecules confer disease protection or susceptibility remain relatively unresolved. We propose to directly examine the role of DQ restricted T cells in T1D pathogenesis and protection from disease. This work, which will apply unique reagents and new technologies and extensive collections of DQ-restricted T cell clones and DQ-transfected cell lines will have the following specific aims: Aim 1: To delineate the functional mechanisms of DQ mediated diabetes susceptibility. Aim 2: To delineate the functional mechanisms of DQ mediated diabetes protection. Aim 3: To directly examine the role of DQ restricted T cells in the pathogenesis of T1D. Utilizing DQ2, DQ8, DQ2/8 and DQ6 monomers and multimers and cutting edge techniques such as ex vivo tetramer enrichment and high throughput transcript analysis, we will identify the distinct functional attributes conferred y susceptible HLA-DQ that lead to the breakdown of self-tolerance and opposing attributes conferred by protective HLA-DQ that restore tolerance. We expect that these attributes will include IL-2 and TCR signaling, antigen presentation, and cytokine profile. Utilizing samples from one of the world's largest T1D registry and a formidable collection of longitudinal samples, we will utilize a matched case-control design that is powered (expected power >90 percent) to compare the ability of DQ and DR auto-reactivity to predict T1D status. A secondary attempt will be made to establish the degree of correlation between DQ and DR auto-reactivity. We expect that HLA-DQ responses will provide a more meaningful correlation than HLA-DR responses. Completion of this study will illuminate important early events in the progression of T1D, suggesting important new avenues for therapy and providing a novel biomarker for disease monitoring. PUBLIC HEALTH RELEVANCE: Recent studies have identified numerous genes that are linked to type 1diabetes (T1D), but HLA genes have by far the strongest association with this disease. Utilizing samples from one of the world's largest T1D patient registries and applying unique technologies, we will directly examine the functional role of these genes in T1D. These observations will illuminate important early events in disease progression, providing a new biomarker and suggesting important new avenues for therapy.